CD39 Identifies the CD4 Tumor-Specific T-cell Population in Human Cancer.

The accumulation of tumor-specific CD4 and CD8 effector T cells is key to an effective antitumor response. Locally, CD4 T cells promote the recruitment and effector function of tumor-specific CD8 T cells and activate innate killer cells in the tumor. Here, we show that tumor-specific CD4 T cells were predominantly present in the CD39 subset of tumor-infiltrating lymphocytes (TIL). The CD39 CD4 and CD8 TILs were detected in three different tumor types, and displayed an activated (PD-1, HLA-DR) effector memory phenotype. CD4CD39 single-cell RNA-sequenced TILs shared similar well-known activation, tissue residency, and effector cell-associated genes with CD8CD39CD103 TILs. Finally, analysis of directly cell-sorted and expanded pure populations of CD39-positive and negative CD4 and CD8 TILs revealed that tumor-specific antigen reactivity was almost exclusively detected among CD39 cells. Immunotherapy of cancer is based on the activation of tumor-reactive CD4 and CD8 T cells. We show that the expression of CD39 can be used to identify, isolate, and expand tumor-reactive T-cell populations in cancers.